Psoriasis
Psoriasis is a common skin disease characterized by thickened patches of inflamed, red skin covered with thick, silvery scales. Psoriasis occurs in a variety of forms that differ in their intensity, duration, location, shape and pattern of scales. The elbows and knees are the most common areas affected by psoriasis. It often appears in the same place on both sides of the body. The patches can range in size from smaller than a coin to larger than a hand. The most common forms of psoriasis are plaque psoriasis, the most common form, characterized by raised, inflamed, red lesions covered with a silvery-white buildup of dead skin cells (scales) and primarily found on the trunk, elbows, knees, scalp and finger or toe nails; pustular psoriasis, a rare form characterized by small pustules (whitehead-like lesions) found all over the body or confined to the palms, soles and other isolated areas of the body; guttate psoriasis, occurring most frequently in children and characterized by numerous small, red, drop-like scaly macules that develop rapidly over a wide area of skin, and inverse psoriasis, occurring in the armpit, under the breast, in skin folds, around the groin, in the cleft between the buttocks and around the genitals, which lacks the thick scale seen in other forms of psoriasis.
Psoriasis can be classified as mild, moderate, or severe. Mild psoriasis is considered to be scaling over less than 5-10 percent of the body, moderate psoriasis is considered to be scaling over 10 to 20 percent of the body and severe psoriasis is considered to be scaling over 20 percent of the body. In 5 percent of all psoriasis sufferers, arthritis will develop. This condition is called psoriatic arthritis. Arthritis is inflammation of a joint, usually accompanied by pain, swelling and changes in joint structure.
Psoriasis is a chronic and relapsing inflammatory disease of the skin associated with various immunologic abnormalities. Approximately 30% of psoriasis patients also have joint involvement, indicative of psoriatic arthritis. Genes and environment play a key role in the pathogenesis of these diseases: genome-wide linkage scans have notably revealed some overlap with psoriasis and atopic dermatitis susceptibility loci.
Many types of cells, including lymphocytes, dendritics APCs (antigen presenting cells), NKT (natural killer T) cells, neutrophils, mast cells, keratinocytes and fibroblasts are supposedly involved in the pathogenesis of psoriasis. Chronic psoriasis is in particular characterized by prominent skin infiltration by neutrophils and microabscess formation. IL-8 was found to be expressed in the neutrophils of psoriasis, suggesting a role for IL-8 in the formation of the microabcesses and pustules. Further, several studies suggest that increased levels of IL-8 expressed in both neutrophils and keratinocytes of psoriatic plaques play a contributing role in the migration of mast cells to lesion sites, the number of which is drastically increased at sites of psoriatic inflammation. Considering their role of multifactorial immune effector cells, mast cells are thus believed to play an essential role in perpetuating the inflammatory process of psoriasis. IL-17 and IL-23 are also known to play a major role in the psoriasis pathogenesis. It has in particular been demonstrated that mast cells and neutrophils are the predominant cell types containing IL-17 in human skin. Furthermore, IL-23 and IL-1β were found to induce mast cell extracellular trap formation and degranulation of human mast cells, suggesting a central role of IL-17 release in the pathogenesis of psoriasis.
Known psoriasis treatments may generally be classified in 3 major categories: topical treatments, systemic treatments and ultraviolet (UV) light therapy.
Topical treatments include emollients, such as creams, ointments, petrolatum, paraffin and hydrogenate vegetable oils, which reduce scaling; salicylic acid, which softens scales, facilitate their removal and increases adsorption of other topical agents; coal tar preparations, which are anti-inflammatory and decrease keratinocyte hyperproliferation; anthralin, which is a topical antiproliferative and anti-inflammatory agent; corticosteroids, which may be used topically or injected; vitamin D3 analogs, that induce normal keratinocyte proliferation and differentiation; calcineurin inhibitors; and tazarotene, a topical retinoid.
Systemic treatments include treatments with methotrexate; systemic retinoids (e.g., acitretin, isotretinoin), which are indicated for severe and recalcitrant cases of psoriasis vulgaris, pustular psoriasis and hyperkeratoticpalmoplantar psoriasis; immunosuppressants, such as Cyclosporineis; and immunomodulatory agents, such as TNF-α inhibitors (etanercept, adalimumab, infliximab), the T-cell modulator alefacept and Ustekinumab, a human monoclonal antibody that targets IL-12 and IL-23.
Finally, UV light therapy is typically used in patients with extensive psoriasis. Whereas the corresponding mechanism of action remains unknown, UVB light reduces DNA synthesis and can induce mild systemic immunosuppression. Further, a treatment (PUVA) also combines the administration of methoxypsoralen, a photosensitizer, with exposure to long-wave UVA light (330 to 360 nm): this results in an antiproliferative effect and also helps to normalize keratinocyte differentiation. Combined administration of retinoids and exposure to UV light, exposure to single NBUVB light (311 to 312 nm) or exposure to single excimer laser (308-nm) are also known methods for treating psoriasis.
Atopic Dermatitis
Atopic dermatitis, also currently known under the names “atopic eczema”, “neurodermitis” or “prurigo Besnier” is a type of inflammatory, relapsing and pruritic skin disorders, the causes of which remain unknown. Atopic dermatitis may affect any part of the body, while being preferably localized on the hands and feet, on the ankles, wrists, face, neck and upper chest. Symptoms may vary but usually comprise red, inflamed and itchy rash and can develop into raised and painful bumps. Atopic dermatitis generally occurs together with other atopic diseases like hay fever, asthma and allergic conjunctivitis, and is often confused with psoriasis. The skin of patients with atopic dermatitis reacts abnormally and easily to irritants, food and environmental allergens.
Although there is no cure known for atopic dermatitis, treatments recommended for psoriasis may provide short-time alternatives for patients.
Urticaria
Urticaria, commonly referred to as “hives”, is characterized by pale red, raised, itchy bumps. Causes for urticaria may be from allergic but also from non-allergic origins, and usually remain unknown. The majority of chronic hives cases have an idiopathic origin, caused by an autoimmune reaction. The underlying molecular mechanism possibly consists in the release of histamine or of cytokines from cutaneous mast cells, thereby resulting in fluid leakage from superficial blood vessels, such as capillaries leakage in the dermis. The edema formed persists until the interstitial fluid is adsorbed into the surrounding cells. To this day, no curative treatment is known. Antihistamines, such as diphenhydramine or tricyclic antioxydepressants, such as doxepin, may be used in therapy, also involving side effects. Corticosteroids such as prednisone are used for treating severe outbreaks and topical creams such as hydrocortisone, fluocinonide or desonide may also be prescribed for relieving itching.
WO 03/051287 discloses a composition for reducing, treating or preventing at least one adverse effect of ionizing radiation by topical application, said composition comprising a mixture of at least one non-flavonoid antioxidant and at least one flavonoid and wherein at least one component is obtained from green tea. The exemplified composition of patent application WO 03/05187 comprises quercetin as flavonoid and a mixture of vitamin A, vitamin E acetate, ascorbyl palmitate and lipoic acid as non-flavonoid antioxidant. The patients self-evaluated the effects of the administration of this composition and noted less severe radiation dermatitis after radiation therapy.
US2005/249761 relates to a topical composition for the prophylaxis and/or treatment of skin diseases and/or inflammation reactions of the skin and can also be used for the cosmetic care of the skin. This composition comprises aryl oxime and bisabolol, and may further include adjuvants and/or excipients. Aryl oximes are known to be useful for the treatment of skin inflammation but are difficult to formulate. In US patent application US2005/249761, it was shown that the use of bisabolol enables their stabilization while reinforcing the anti-inflammatory action. However, no evaluation of the efficacy of this composition is provided.
Kirchner et al (Mediators of inflammation, 2013, 2013:710239) describes that flavonoids, including (+)-catechin hydrate, inhibit the production of reactive oxygen species (ROS) and the formation of neutrophil extracellular traps (NETs). In particular, this article discloses the role of NETs and NET components in autoimmune diseases such as psoriasis. However, Kirchner et al does not disclose the use of compositions comprising dihydroquercetin for treating the effects associated with skin inflammatory disorders.
Bito et al (FEBS Letters, 2002, 520(1-3):145-152) discloses the inhibition of IFNγ-induced ICAM-1 protein and mRNA expression by taxifolin in human keratinocytes. Bito et al thus suggests the therapeutic potential of taxifolin in skin pathological conditions. However, Bito et al fails to disclose any skin pathological conditions. In particular, Bito et al does not mention diseases characterized by inappropriate immune response, such as psoriasis, atopic dermatitis and/or urticaria.
Patent application No. EP12181058.4 discloses companion cosmetic treatments for assisting patients in the management of their therapy-related cutaneous discomfort. This application in particular describes cosmetic compositions comprising dihydroquercetin, α-tocopherol and bisabolol for treating the discomfort resulting from skin irritation, inflammation or cutaneous erythema that are provoked by a treatment, and preferably those resulting from anticancer radiotherapies and/or chemotherapy. Patent application No. EP12181058.4 nevertheless fails to disclose the use of compositions comprising dihydroquercetin for treating the effects associated with skin inflammatory disorders, and more particularly with diseases characterized by inappropriate immune response, such as psoriasis, atopic dermatitis and/or urticaria.
Even though several treatments are proposed for treating psoriasis, atopic dermatitis and/or urticaria, none of these treatments actually provide remedies which could both alleviate the effects associated with these diseases over mid- to long-term, and which would be devoid of deleterious secondary effects.
There is thus a need to provide solutions for treating the effects associated with skin inflammatory disorders, and more particularly with diseases characterized by inappropriate immune response, including skin inflammation, psoriasis, atopic dermatitis and/or urticaria. The present invention aims at reaching this need, and relates to the use of compositions suitable for being administered topically to patients.
Advantageously, the compositions of the invention are safe, do not contain phototoxic and/or photosensibilizing components, show no toxicity. They are also effective in treating the effects associated with skin inflammation and associated with diseases characterized by inappropriate immune response, such as psoriasis, atopic dermatitis and/or urticaria.
The composition of the invention presents the advantage to have a high stability and preservability. Moreover, the composition of the invention produces a pleasant feeling when applied on skin.